Treatment of NAFLD and NASH

ABSTRACT

Treatment of NAFLD and NASH by therapy with MBX-8025 or an MBX-8025 salt.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/22,379, filed Dec. 17, 2018, now U.S. Pat. No. 10,342,770; which is acontinuation of U.S. application Ser. No. 15/943,936, filed Apr. 3,2018, now U.S. Pat. No. 10,188,620; which is a continuation of U.S.application Ser. No. 15/447,895, filed Mar. 2, 2017, now U.S. Pat. No.9,962,346; which is a continuation of U.S. application Ser. No.15/171,910, filed Jun. 2, 2016, now U.S. Pat. No. 9,616,039; which is acontinuation of U.S. application Ser. No. 14/684,100, filed Apr. 10,2015, now U.S. Pat. No. 9,383,181. U.S. application Ser. No. 14/684,100claims the priority under 35 USC 119(e) of U.S. Application No.61/978,335, filed Apr. 11, 2014, entitled “Treatment of NAFLD and NASH”,which is incorporated into U.S. application Ser. No. 14/684,100 byreference.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to the treatment of non-alcoholic fatty liverdisease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Description of the Related Art

NAFLD and NASH

Non-alcoholic fatty liver disease (NAFLD) is a disorder affecting asmany as 1 in 3-5 adults and 1 in 10 children in the United States, andrefers to conditions where there is an accumulation of excess fat in theliver of people who drink little or no alcohol. The most common form ofNAFLD is a non-serious condition called hepatic steatosis (fatty liver),in which fat accumulates in the liver cells: although this is notnormal, by itself it probably does not damage the liver. NAFLD mostoften presents itself in individuals with a constellation of riskfactors called the metabolic syndrome, which is characterized byelevated fasting plasma glucose (FPG) with or without intolerance topost-prandial glucose, being overweight or obese, high blood lipids suchas cholesterol and triglycerides (TGs) and low high-density lipoproteincholesterol (HDL-C) levels, and high blood pressure; but not allpatients have all the manifestations of the metabolic syndrome. Obesityis thought to be the most common cause of NAFLD; and some expertsestimate that about two-thirds of obese adults and one-half of obesechildren may have fatty liver. The majority of individuals with NAFLDhave no symptoms and a normal physical examination (although the livermay be slightly enlarged); children may exhibit symptoms such asabdominal pain and fatigue, and may show patchy dark skin discoloration(acanthosis nigricans). The diagnosis of NAFLD is usually firstsuspected in an overweight or obese person who is found to have mildelevations in their liver blood tests during routine testing, thoughNAFLD can be present with normal liver blood tests, or incidentallydetected on imaging investigations such as abdominal ultrasound or CTscan. It is confirmed by imaging studies, most commonly a liverultrasound or magnetic resonance imaging (MRI), and exclusion of othercauses.

Some people with NAFLD may develop a more serious condition callednon-alcoholic steatohepatitis (NASH): about 2-5% of adult Americans andup to 20% of those who are obese may suffer from NASH. In NASH, fataccumulation in the liver is associated with inflammation and differentdegrees of scarring. NASH is a potentially serious condition thatcarries a substantial risk of progression to end-stage liver disease,cirrhosis and hepatocellular carcinoma. Some patients who developcirrhosis are at risk of liver failure and may eventually require aliver transplant.

NAFLD may be differentiated from NASH by the NAFLD Activity Score (NAS),the sum of the histopathology scores of a liver biopsy for steatosis (0to 3), lobular inflammation (0 to 2), and hepatocellular ballooning (0to 2). A NAS of <3 corresponds to NAFLD, 3-4 corresponds to borderlineNASH, and >5 corresponds to NASH. The biopsy is also scored for fibrosis(0 to 4).

NASH is a leading cause of end-stage liver disease; while NAFLD, and toan even greater degree NASH, are intimately related to states of themetabolic syndrome, including insulin resistance (pre-diabetes) and type2 diabetes mellitus (T2DM), and abdominal obesity. T2DM has been themost prominent predictor for a poor prognosis in NAFLD, whereas elevatedliver enzymes are considered unreliable. NASH develops much morefrequently in the presence of longstanding T2DM, and the majority ofpatients with cryptogenic cirrhosis are obese and/or diabetic. Studieshave demonstrated that 60% of patients with T2DM and NAFLD hadbiopsy-proven NASH, and that advanced hepatic fibrosis was present in75% of those with diabetes and hypertension compared to only 7% withouteither condition. Haukeland, “Abnormal glucose tolerance is a predictorof nonalcoholic steatohepatitis and fibrosis in patients withnon-alcoholic fatty liver disease”, Scand J. Gastroenterol., 40,1469-1477 (2005), reported that impaired glucose tolerance (IGT) andT2DM were the only independent risk factors for severe NAFLD and NASH,increasing the odds ratio almost 4-fold. Mofrad, “Clinical andhistological spectrum of nonalcoholic fatty liver disease associatedwith normal ALT levels”, Hepatology, 37, 1286-1292 (2003), reported astudy that demonstrated the lack of predictive value for elevated livertransaminases to diagnose NASH in patients with NAFLD and found T2DM tobe the only factor independently associated with an increased risk ofadvanced fibrosis. Thus, NASH is an overlooked complication of T2DM thatis frequently associated with fibrosis and in approximately 10% ofpatients results in cirrhosis; while the risk of hepatocellularcarcinoma is also increased in patients with T2DM and NASH. Patientswith NAFLD and NASH usually demonstrate mixed dyslipidemia and the othermetabolic derangements described above, including an atherogeniclow-density lipoprotein (LDL) phenotype consisting of predominantly ofsmall dense particles. Both metabolic syndrome and NAFLD/NASH arecharacterized by increased cardiovascular inflammation as measured byelevations in high sensitivity C-reactive protein (hsCRP) and otherinflammatory cytokines.

There is significant worldwide incidence of obesity, metabolic syndrome,pre-diabetes and diabetes, with the prevalence of diabetes worldwidepredicted to double to 366 million by 2030. The US population withdiabetes has been estimated at 25.4 million (11.5% prevalence) in 2011and 37.7 million (14.5%) by 2031, with 20.2% of Hispanic adults havingdiabetes. Because approximately 70% of persons with T2DM have a fattyliver, and the disease follows a more aggressive course withnecroinflammation and fibrosis (i.e., NASH) in diabetes, theepidemiology of diabetes suggests significant increases in NASH andchronic liver disease. Using MRI for the noninvasive assessment ofhepatic steatosis, the prevalence of NAFLD, when defined as liverfat >5%, has been estimated to be 34% in the USA or approximately 80million people, and as many as two out of three obese subjects. However,this prevalence is believed to be much higher in T2DM. In a series of107 unselected patients with T2DM, the prevalence of NAFLD by MRI was76%, which is similar to recent studies from Italy and Brazil. Recentstudies have indicated that the prevalence of NAFLD is rapidly rising inobese children and adolescents, especially those of Hispanic ancestry.

Treatments for NAFLD and NASH

There are no drugs currently approved to prevent or treat NAFLD or NASH.A number of pharmacological interventions have been tried in NAFLD/NASHbut with overall limited benefit.

Antioxidant agents may arrest lipid peroxidation and cytoprotectiveagents stabilize phospholipid membranes, but agents tried unsuccessfullyor with only modest benefit so far include ursodeoxycholic acid,vitamins E (α-tocopherol) and C, and pentoxifylline, among others.Weight-loss agents such as orlistat have had no significant benefitcompared to just the use of diet and exercise to achieve weight loss(“weight loss alone”). Most weight-loss studies in NAFLD/NASH have beenpilot studies of short duration and limited success, reporting only amodest improvement in necroinflammation or fibrosis. A randomized,double-blind, placebo-controlled 6-month trial (Belfort, “Aplacebo-controlled trial of pioglitazone in subjects with nonalcoholicsteatohepatitis”, N. Engl. J. Med., 355, 2297-2307 (2006)) of weightloss alone against pioglitazone, a thiazolidinedione peroxisomeproliferator-activated receptor-γ (PPARγ) agonist and insulinsensitizer, failed to demonstrate any improvement for weight loss alone,but treatment with pioglitazone improved glycemic control, insulinsensitivity, indicators of systemic inflammation (including hsCRP, tumornecrosis factor-α, and transforming growth factor-β), and liverhistology in patients with NASH and IGT or T2DM. Treatment withpioglitazone also ameliorated adipose, hepatic, and muscle IR, and wasassociated with an approximately 50% decrease in necroinflammation(p<0.002) and a 37% reduction in fibrosis (p=0.08). Improvement inhepatocellular injury and fibrosis has been recently reported in anothercontrolled trial with pioglitazone of 12 months duration. In contrast,while the first randomized clinical study with rosiglitazone, the otherthiazolidinedione approved for diabetes treatment, in NASH demonstrateda reduction in IR, plasma alanine aminotransferase (ALT) levels andsteatosis, rosiglitazone treatment had no significant effect onnecrosis, inflammation, or fibrosis. A preliminary report of the 2-year,open-label follow-up of this trial was also disappointing, with nosignificant benefit from rosiglitazone treatment. Thus, thepharmacological agent with the most robust efficacy in NASH ispioglitazone. Unfortunately, pioglitazone is also associated with asignificantly increased risk of weight gain, edema, congestive heartfailure, and osteoporotic fractures in both women and men.

GW510516, a potent peroxisome proliferator-activated receptor-δ (PPARδ)agonist, ameliorated diet-induced obesity and insulin resistance innormal mice, an effect accompanied by enhanced metabolic rate and fattyacid β-oxidation. It also markedly improved diabetes as evidenced bysubstantial reductions in both glucose and insulin levels in geneticallyobese ob/ob mice. GW510516 has been shown in two Phase 1 studies inhealthy subjects to reduce TGs, low-density-lipoprotein cholesterol(LDL-C), apolipoprotein B (apoB), and insulin levels, and improve HDL-Cand insulin sensitivity, with one of the studies also showing a 20%reduction in hepatic fat; while a later study confirmed these effects indyslipidemic subjects with abdominal obesity (reduction in hepatic fatby 20%, 30% decrease in fasting TGs, 26% reduction in apoB, 23%reduction in LDL-C, 40% reduction in fasting non-esterified fatty acids,and 11% decrease in fasting insulin). However, development of GW510516was discontinued after observations in animal studies of its associationwith the rapid development of cancers in several organs.

The dual peroxisome proliferator-activated receptor-α/peroxisomeproliferator-activated receptor-δ (PPARα/δ) agonist GFT505 haspreferential α (EC₅₀=6 nM) and secondary δ (EC₅₀=47 nM) agonistactivity. The lipid-modifying efficacy of GFT505 has been confirmed inboth healthy subjects, as well as in patients with T2DM, combinedabdominal obesity and mixed dyslipidemia, combined abdominal obesity andpre-diabetes, atherogenic dyslipidemia, and insulin resistance. Theseeffects include reduction in TGs, non-HDL-C, and total cholesterol,LDL-C, and apoB; and increases in HDL-C. Preclinical studies in rodentmodels of NAFLD/NASH demonstrated that GFT505 treatment decreasedhepatic steatosis, inflammation, and fibrosis, and decreased liverdysfunction markers; while in clinical studies GFT505 has been reportedto decrease a range of liver dysfunction markers including ALT, alkalinephosphatase (ALP), and γ-glutamyl transferase (GGT). A 1-year liverbiopsy-based Phase2b trial in NASH initially recruited patients fortreatment with 80 mg/day of GFT505 or placebo, with an interim safetyanalysis at 6 months showing no safety issue that compromised theongoing study; and a second recruitment phase has selected patients fortreatment with 120 mg/day of GFT505 or placebo.

Obeticholic acid (OCA, 6α-ethylchenodeoxycholic acid), a semi-syntheticbile acid analog that is a highly potent farnesoid X receptor agonist,was studied in a Phase 2 study for NASH, the FLINT study, sponsored bythe US National Institute of Diabetes and Digestive and Kidney Diseases.That study was halted early in January 2014, after about half of the 283subjects had completed the study, when a planned interim analysis showedthat the primary endpoint had been met. The treatment (OCA 25 mg/day for72 weeks) resulted in a highly statistically significant improvement(p=0.0024 on an intention-to-treat basis, compared to placebo) in theprimary histological endpoint, defined as a decrease in NAS of at leasttwo points with no worsening of fibrosis.

Notwithstanding the initial benefits reported for GFT505 and OCA, therestill remains a significant unmet clinical need for an effective andwell-tolerated drug that can prevent or slow down the progression ofNAFLD and NASH.

MBX-8025

MBX-8025 is the compound of the formula

MBX-8025 has the chemical name(R)-2-(4-((2-ethoxy-3-(4-(trifluoromethyl)phenoxy)propyl)-thio)-2-methylphenoxy)aceticacid [IUPAC name as generated by CHEMDRAW ULTRA 12.0]. MBX-8025 and itssynthesis, formulation, and use is disclosed in, for example, U.S. Pat.No. 7,301,050 (compound 15 in Table 1, Example M, claim 49), U.S. Pat.No. 7,635,718 (compound 15 in Table 1, Example M), and U.S. Pat. No.8,106,095 (compound 15 in Table 1, Example M, claim 14). Lysine(L-lysine) salts of MBX-8025 and related compounds are disclosed in U.S.Pat. No. 7,709,682 (MBX-8025 L-lysine salt throughout the Examples,crystalline forms claimed). MBX-8025 has the InternationalNonproprietary Name seladelpar [“Recommended INN: List 77”, WHO DrugInformation, vol. 31(1), pp. 128-129 (2017)].

MBX-8025 is an orally active, potent (2 nM) agonist of PPARδ, It isspecific (>600-fold and >2500-fold compared with PPARα and PPARγreceptors). PPARγ activation stimulates fatty acid oxidation andutilization, improves plasma lipid and lipoprotein metabolism, glucoseutilization, and mitochondrial respiration, and preserves stem cellhomeostasis. According to U.S. Pat. No. 7,301,050, PPARδ agonists, suchas MBX-8025, are suggested to treat PPARδ-mediated conditions, including“diabetes, cardiovascular diseases, Metabolic X syndrome,hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity”,with dyslipidemia said to include hypertriglyceridemia and mixedhyperlipidemia.

A Phase 2 study of MBX-8025 L-lysine dihydrate salt in mixeddyslipidemia (6 groups, 30 subjects/group: once daily placebo,atorvastatin (ATV) 20 mg, or MBX-8025 L-lysine dihydrate salt at 50 or100 mg (calculated as the free acid) capsules alone or combined with ATV20 mg, for 8 weeks) has been reported by Bays et al., “MBX-8025, A NovelPeroxisome Proliferator Receptor-6 Agonist: Lipid and Other MetabolicEffects in Dyslipidemic Overweight Patients Treated with and withoutAtorvastatin”, J. Clin. Endocrin. Metab., 96(9), 2889-2897 (2011) andChoi et al., “Effects of the PPAR-δ agonist MBX-8025 on atherogenicdyslipidemia”, Atherosclerosis, 220, 470-476 (2012). Compared toplacebo, MBX-8025 alone and in combination with atorvastatinsignificantly (P<0.05) reduced apoB100 by 20-38%, LDL by 18-43%,triglycerides by 26-30%, non-HDL-C by 18-41%, free fatty acids by16-28%, and high-sensitivity C-reactive protein by 43-72%; it raisedHDL-C by 1-12% and also reduced the number of patients with themetabolic syndrome and a preponderance of small LDL particles. WhileMBX-8025 at 100 mg/day reduced LDL-C by 22% over the total populationtreated, the percentage reduction in LDL-C increased to 35% in thetertile with the highest starting LDL-C levels (187-205 mg/dL), andtrend analysis on individual patient data confirmed a positivecorrelation between percentage reduction in LDL-C and starting LDL-Clevel. MBX-8025 reduced LDL-S/VS by 40-48% compared with a 25% decreasewith atorvastatin; and MBX-8025 increased LDL-L by 34-44% compared witha 30% decrease with atorvastatin. MBX-8025 significantly reducedalkaline phosphatase by 32-43%, compared to reductions of only 4% in thecontrol group and 6% in the ATV group; and significantly reducedγ-glutamyl transpeptidase by 24-28%, compared to a reduction of only 3%in the control group and an increase of 2% in the ATV group. ThusMBX-8025 corrects all three lipid abnormalities in mixed dyslipidemia:lowers TGs and LDL and raises HDL, selectively depletes small dense LDLparticles (92%), reduces cardiovascular inflammation, and improves othermetabolic parameters: increases insulin sensitivity (lowers HOMA-IR,fasting plasma glucose, and insulin), lowers γ-glutamyl transpeptidaseand alkaline phosphatase, significantly (>2-fold) reduces the percentageof subjects meeting the criteria for metabolic syndrome, and trendstowards a decrease in waist circumference and increase in lean bodymass. As explained in US Patent Application Publication No.2010-0152295, MBX-8025 converts LDL particle size pattern I to patternA; and from pattern B to pattern I or A, where LDL particle size patternB is a predominant LDL particle size of less than 25.75 nm, pattern I isa predominant LDL particle size of from 25.75 nm to 26.34 nm, andpattern A is a predominant LDL particle size of greater than 26.34 nm,where the LDL particle size is measured by gradient-gel electrophoresis.

The disclosures of the documents referred to in this application areincorporated into this application by reference.

SUMMARY OF THE INVENTION

This invention is a method of treatment of NAFLD and NASH, comprisingadministration of MBX-8025 or an MBX-8025 salt.

Because MBX-8025 effectively enhances fatty acid β-oxidation and lowersserum apoB, LDL-C, TGs, non-esterified fatty acids, and hsCRP inclinical and in non-clinical studies, while raising HDL-C in humans, itsuse will be effective in the treatment of NAFLD and NASH. Further,unlike fenofibrate, MBX-8025 will significantly decrease hepatic fat(assessed by MRI), reduce transaminases, multiple inflammatorycytokines, the hepatocellular apoptosis marker CK18, improve the LDLphenotype, and demonstrate improvement in multiple glycemic parametersincluding glycated hemoglobin (HbA1c), FPG, fasting insulin, andHOMA-IR. Because the presence of >6% hepatic fat content by MRI in obesesubjects with insulin resistance is very predictive of both NAFLD andNASH, reduction of hepatic fat by treatment with MBX-8025 will besignificant in the treatment of NAFLD and NASH.

Preferred embodiments of this invention are characterized by thespecification and by the features of claims 1 to 14 of this applicationas filed.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“NAFLD and NASH” and their treatment are described in paragraphs [0003]through [0013] the Description of the Related Art, under “NAFLD andNASH” and “Treatments for NAFLD and NASH”.

A “therapeutically effective amount” of MBX-8025 or an MBX-8025 saltmeans that amount which, when administered to a human for treating NAFLDor NASH, is sufficient to effect treatment for the NAFLD or NASH.“Treating” or “treatment” of NAFLD or NASH in a human includes one ormore of:

-   (1) preventing or reducing the risk of developing NAFLD or NASH,    i.e., causing the clinical symptoms of NAFLD or NASH not to develop    in a subject who may be predisposed to NAFLD or NASH but who does    not yet experience or display symptoms of the NAFLD or NASH (i.e.    prophylaxis);-   (2) inhibiting NAFLD or NASH, i.e., arresting or reducing the    development of NAFLD or NASH or its clinical symptoms; and-   (3) relieving NAFLD or NASH, i.e., causing regression, reversal, or    amelioration of the NAFLD or NASH or reducing the number, frequency,    duration or severity of its clinical symptoms. The therapeutically    effective amount for a particular subject varies depending upon the    health and physical condition of the subject to be treated, the    extent of the NAFLD or NASH, the assessment of the medical    situation, and other relevant factors. It is expected that the    therapeutically effective amount will fall in a relatively broad    range that can be determined through routine trial.

“MBX-8025” is described in paragraphs [0015] through [0018] theDescription of the Related Art, under “MBX-8025”.

Salts (for example, pharmaceutically acceptable salts) of MBX-8025 areincluded in this invention and are useful in the compositions, methods,and uses described in this application. These salts are preferablyformed with pharmaceutically acceptable acids. See, for example,“Handbook of Pharmaceutically Acceptable Salts”, Stahl and Wermuth,eds., Verlag Helvetica Chimica Acta, Zurich, Switzerland, for anextensive discussion of pharmaceutical salts, their selection,preparation, and use. Unless the context requires otherwise, referenceto MBX-8025 is a reference both to the compound and to its salts.

Because MBX-8025 contains a carboxyl group, it may form salts when theacidic proton present reacts with inorganic or organic bases. Typicallythe MBX-8025 is treated with an excess of an alkaline reagent, such ashydroxide, carbonate or alkoxide, containing an appropriate cation.Cations such as Na⁺, K⁺, Ca²⁺, Mg²⁺, and NH₄ ⁺ are examples of cationspresent in pharmaceutically acceptable salts. Suitable inorganic bases,therefore, include calcium hydroxide, potassium hydroxide, sodiumcarbonate and sodium hydroxide. Salts may also be prepared using organicbases, such as salts of primary, secondary and tertiary amines,substituted amines including naturally-occurring substituted amines, andcyclic amines, including isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and the like. As noted in the Description of theRelated Art, under “MBX-8025”, MBX-8025 is currently formulated as itsL-lysine dihydrate salt; and MBX-8025 has also been studied in clinicaltrials as its calcium salt.

“Comprising” or “containing” and their grammatical variants are words ofinclusion and not of limitation and mean to specify the presence ofstated components, groups, steps, and the like but not to exclude thepresence or addition of other components, groups, steps, and the like.Thus “comprising” does not mean “consisting of”, “consistingsubstantially of”, or “consisting only of”; and, for example, aformulation “comprising” a compound must contain that compound but alsomay contain other active ingredients and/or excipients.

Formulation and Administration

The MBX-8025 may be administered by any route suitable to the subjectbeing treated and the nature of the subject's condition. Routes ofadministration include administration by injection, includingintravenous, intraperitoneal, intramuscular, and subcutaneous injection,by transmucosal or transdermal delivery, through topical applications,nasal spray, suppository and the like or may be administered orally.

Formulations may optionally be liposomal formulations, emulsions,formulations designed to administer the drug across mucosal membranes ortransdermal formulations. Suitable formulations for each of thesemethods of administration may be found, for example, in “Remington: TheScience and Practice of Pharmacy”, 20th ed., Gennaro, ed., LippincottWilliams & Wilkins, Philadelphia, Pa., U.S.A. Because MBX-8025 is orallyavailable, typical formulations will be oral, and typical dosage formswill be tablets or capsules for oral administration. As mentioned in theDescription of the Related Art, under “MBX-8025”, MBX-8025 has beenformulated in capsules for clinical trials.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, preferably in unit dosage form suitable for single administrationof a precise dosage. In addition to an effective amount of the MBX-8025,the compositions may contain suitable pharmaceutically-acceptableexcipients, including adjuvants which facilitate processing of theactive compounds into preparations which can be used pharmaceutically.“Pharmaceutically acceptable excipient” refers to an excipient ormixture of excipients which does not interfere with the effectiveness ofthe biological activity of the active compound(s) and which is not toxicor otherwise undesirable to the subject to which it is administered.

For solid compositions, conventional excipients include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talc, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. Liquid pharmacologically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in water or an aqueous excipient, such as, for example, water,saline, aqueous dextrose, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliaryexcipients such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, etc.

For oral administration, the composition will generally take the form ofa tablet or capsule, or it may be an aqueous or nonaqueous solution,suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use will generallyinclude one or more commonly used excipients such as lactose and cornstarch. Lubricating agents, such as magnesium stearate, are alsotypically added. When liquid suspensions are used, the active agent maybe combined with emulsifying and suspending excipients.

If desired, flavoring, coloring and/or sweetening agents may be added aswell. Other optional excipients for incorporation into an oralformulation include preservatives, suspending agents, thickening agents,and the like.

Typically, a pharmaceutical composition of MBX-8025, or a kit comprisingcompositions of MBX-8025, is packaged in a container with a label, orinstructions, or both, indicating use of the pharmaceutical compositionor kit in the treatment of NAFLD and/or NASH.

A suitable amount of MBX-8025 (calculated as the free acid) for oraldosing will be 20-200 mg/day, preferably 50-100 mg/day, for an adultsubject with NAFLD or NASH, depending on the disease and stage ofdisease and factors such as hepatic and renal function. That is, asuitable amount of MBX-8025 for oral dosing will be similar to theamounts employed in clinical trials; though it is possible that thetherapeutically effective amount may be higher in severe cases of NAFLDor NASH. Suitable reductions in dose toward the lower end of the outerrange above will be made for subjects who are children, depending onsuch additional factors as age and body mass.

A person of ordinary skill in the art of the treatment of NAFLD or NASHwill be able to ascertain a therapeutically effective amount of theMBX-8025 or an MBX-8025 salt for a particular stage of disease toachieve a therapeutically effective amount without undue experimentationand in reliance upon personal knowledge and the disclosure of thisapplication.

EXAMPLE

Subjects with NAFLD or NASH are treated with doses of either 50 or 100mg/day of MBX-8025 for 6 months. Subjects are permitted their usualother medications (e.g. antidiabetic medications such as metformin orsulfonamides) but not glitazones, PPAR agonists, OCA, or similarmedications. The subjects are assessed before the study, and atintervals during the study, such as every 4 weeks during the study and 4weeks after the last dose of the MBX-8025 therapy, for safety andpharmacodynamic evaluations.

MRIs of the subjects' livers are taken every 4 weeks during the studyand 4 weeks after completion of MBX-8025 dosing, to determine hepaticfat; and liver biopsies are taken before the study (to establish thediagnosis) and 4 weeks after completion of MBX-8025 dosing. At eachvisit, after a 12-hour fast, blood is drawn and urine collected; and astandard metabolic panel, complete blood count, and standard urinalysisare performed. Blood is analyzed for total cholesterol, HDL-C, LDL-C,VLDL-C, TGs, apoB, and liver transaminases. The subjects also maintainhealth diaries, which are reviewed at each visit. The subjects show adose-related improvement in their disease, as manifested by, forexample, MRI and liver biopsy.

While this invention has been described in conjunction with specificembodiments and examples, it will be apparent to a person of ordinaryskill in the art, having regard to that skill and this disclosure, thatequivalents of the specifically disclosed materials and methods willalso be applicable to this invention; and such equivalents are intendedto be included within the following claims.

What is claimed is:
 1. A method for reducing alkaline phosphatase (ALP)or γ-glutamyl transpeptidase (GGT) in a subject having a disease that isnon-alcoholic fatty liver disease (NAFLD) or non-alcoholicsteatohepatitis (NASH), comprising administering a therapeuticallyeffective amount of seladelpar or a salt thereof to the subject.
 2. Amethod for reducing alkaline phosphatase (ALP) or γ-glutamyltranspeptidase (GGT) in a subject having a disease that is non-alcoholicfatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH),comprising orally administering a therapeutically effective amount ofseladelpar or a salt thereof to the subject.
 3. The method of claim 2where the daily dose of the seladelpar or a salt thereof administered tothe subject is 20-200 mg, when the dose is calculated as seladelpar. 4.The method of claim 3 where the daily dose of the seladelpar or a saltthereof administered to the subject is 50-100 mg, when the dose iscalculated as seladelpar.
 5. The method of claim 2 where the seladelparor a salt thereof is administered to the subject once/day.
 6. The methodof claim 2 where the disease is NAFLD.
 7. The method of claim 6 wherethe ALP or GGT is ALP.
 8. The method of claim 6 where the ALP or GGT isGGT.
 9. The method of claim 2 where the disease is NASH.
 10. The methodof claim 9 where the ALP or GGT is ALP.
 11. The method of claim 9 wherethe ALP or GGT is GGT.
 12. A method for reducing alkaline phosphatase(ALP) or γ-glutamyl transpeptidase (GGT) in a subject having a diseasethat is non-alcoholic fatty liver disease (NAFLD) or non-alcoholicsteatohepatitis (NASH), comprising orally administering atherapeutically effective amount of seladelpar L-lysine dihydrate saltto the subject.
 13. The method of claim 12 where the daily dose of theseladelpar L-lysine dihydrate salt administered to the subject is 20-200mg, when the dose is calculated as seladelpar.
 14. The method of claim13 where the daily dose of the seladelpar L-lysine dihydrate saltadministered to the subject is 50-100 mg, when the dose is calculated asseladelpar.
 15. The method of claim 12 where the seladelpar L-lysinedihydrate salt is administered to the subject once/day.
 16. The methodof claim 12 where the disease is NAFLD.
 17. The method of claim 12 wherethe disease is NASH.
 18. The method of claim 12 where the ALP or GGT isALP.
 19. The method of claim 12 where the ALP or GGT is GGT.